Nutlin3a is an Mdm2 inhibitor and is potent to stabilize p53, which is a tumor-suppressor involved in various biological processes such as cell cycle regulation, DNA repair, and apoptosis (see, for example, U.S. Pat. No. 7,705,007 and Science (2004) 303, 844-848).
Caylin2 is a Nutlin-3 analog in which trifluoromethyl groups have been substituted for chlorine on the 2 phenyl rings.
p53 is a tumor-suppressor that is mutated or deleted in more than half of all human tumors. The physiological roles of p53 are versatile, forming a cell cycle checkpoint and functioning in DNA repair, apoptosis, and energy metabolism (Nature (2009) 458:1127-1130). It has been shown that phosphorylations at multiple sites and subsequent proteasomal degradation are important in the regulation of p53 protein levels (Cell (2009) 137; 609-622). p53 ubiquitination required in its degradation is catalyzed by several ubiquitin ligases such as Mdm2, Pirh2, and Cop1 (Cell Death Differ. (2010) 17; 86-92). In particular, the mechanism of regulation of p53 by Mdm2 has been well-analyzed. Because the massive stabilization of p53 was able to induce apoptosis in p53 proficient tumor cells (Nature (1991) 352; 345-347), stabilization of p53 via an inhibition of Mdm2 is one of the attractive strategies for cancer therapy. Recently, it has been reported that small molecular compounds such as Nutlin3a and MI-219 act as cell-permeable Mdm2 antagonists (Science (2004) 303; 844-848, Proc. Natl. Acad. Sci. U.S.A. (2008) 105; 3933-3938), and their analogs have progressed to preclinical development or early phase clinical trials for anti-cancer therapy (Annu. Rev. Pharmacol. Toxicol. (2009) 49; 223-241). Because p53 upregulates anti-oxidant and anti-inflammatory genes (Nat. Med. (2005) 11; 1306-1313, FASEB J (2005) 19; 1030-1032), p53 has a potential to protect from I/R-induced cellular injuries via anti-oxidative and anti-inflammatory responses.
Parp1 is a major enzyme catalyzing poly (ADP-ribosyl) ation, which is a post-translational protein modification. It is involved in replication, DNA repair, and cell death (Cell Mol. Life Sci. (2005) 62, 769-783, Cancer Sci. (2007) 98, 1528-1535). Parp1 is dramatically activated by DNA breaks and then catalyzes poly(ADP-ribosyl)ation on substrate proteins in DNA damage regions, which is required for efficient recruitment of DNA repair factors to the loci (Cell. Biol. (2003) 23, 5919-5927, Nucleic Acids Res. (2007) 35, 7665-7675). On the other hand, over-activation of Parp1 decreases cellular NAD+ and ATP levels, resulting in necrotic cell death caused by breakdown of energy metabolism (Proc. Natl. Acad. Sci. U.S.A. (1999) 96, 13978-13982, Mol. Cell. Biol. (1999) 19, 5124-5133). The involvement of Parp1 in inflammatory responses has also been reported. Ischemia/reperfusion-induced Parp1 over-activation is mediated by production of reactive oxygen species and is involved in NF-kB transactivation (Am. J. Pathol. (2008) 173, 2-13). Furthermore, Parp1 has been also characterized as a useful hallmark of apoptosis because full length Parp1 is cleaved by the apoptotic proteases, caspase-3 and -7, into p85 and p25 fragments during apoptosis (Cancer Res. (1993) 53, 3976-3985, Nature (1994) 371, 346-347). Therefore, Parp1 is an attractive target of cancer chemotherapy and protection from ischemia/reperfusion injury, and several Parp1 inhibitors are being evaluated in clinical trials (J. Med. Chem. (2010) 53, 4561-4584).